| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2005: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2004: ¥2,100,000 (Direct Cost: ¥2,100,000)
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| Research Abstract |
Macrophage colony-stimulating factor (M-CSF) is an essential cytokine for the growth, differentiation and survival of macrophages. There is an increasing knowledge regarding the molecular mechanism positively regulating M-CSF signals. However, negative regulatory mechanisms for M-CSF signals are poorly understood. Given that the perturbation in their balance is one of the triggers for tumorigenesis, the clarification of the negative feedback systems for M-CSF signals is an important issue.
MAIR/TRIM35 is a novel gene that we have isolated as one of genes whose expression are up-regulated by M-CSF stimulation. Structurally, it belongs to RBCC family proteins. We found that MAIR/TRIM induced cell death in a variety of tumor cells. Among four functional domains (RING finger, B-box, coiled-coil, SPRY), both the Ring finger and coiled-coil domains were essential for the apoptosis-inducing function of MAIR/TRIM35. The cell death was associated with the reduction in mitochondrial membrane potential and the activation of caspase-7, -8, and -9 but not caspase-3. MAIR/TRIM35 proteins showed a large granular distribution predominantly in the cytoplasm. Mutants lacking the apoptosis-inducing function did not form such aggregates, indicating that its unique intracellular distribution pattern was a major determinant for the function of MAIR/TRIM35.
In this study, we demonstrated that M-CSF, a growth-promoting cytokine, induced the expression of apoptosis-inducing protein MAIR/TRIM35. Identification of molecules responsible for the function of apoptosis-inducing function will further clarify mechanisms whereby MAIR/TRIM35 induces cell death.
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